Erythropoietin reduces fat mass in female mice lacking estrogen receptor alpha.
Erythropoietin reduces fat mass in female mice lacking estrogen receptor alpha.
复制标题
促红细胞生成素减少缺乏雌激素受体α的雌性小鼠的脂肪量。
DOI：
10.1016/j.molmet.2020.101142
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发表时间：
2021-03
影响因子：
8.1
通讯作者：
Noguchi CT
中科院分区：
文献类型：
--
作者：
Lee J;Walter MF;Korach KS;Noguchi CT
促红细胞生成素(EPO)是红细胞生成所必需的细胞因子，在脂肪代谢调节和血糖控制中起重要作用。高脂饮食(HFD)小鼠的EPO治疗改善了糖耐量，并通过减少雄性和去卵巢雌性的脂肪量而减少了体重增加。在去卵巢的女性HFD期间，EPO治疗减少了脂肪堆积，但补充雌二醇可以消除这种减少，这为雌激素相关的性别特异性EPO在代谢调节中的作用提供了证据。在这项研究中，我们研究了雌激素通过雌激素受体α(ERα)和促红细胞生成素(EPO)调节葡萄糖代谢和脂肪积累的相互作用。采用野生型(WT)小鼠和ERα基因敲除(ERα−/−)和脂肪组织ERα靶向缺失(ERα脂肪KO)模型，观察高脂饮食喂养期间和饮食诱导肥胖后EPO的治疗作用。服用高脂饲料的ERα−/−小鼠表现出脂肪质量增加和糖耐量增加。促红细胞生成素对高脂饮食的治疗减少了雄性WT和ERα−/−小鼠和雌性ERα−/−小鼠的脂肪积累，但不减少雌性WT小鼠的脂肪积累。促红细胞生成素减少了WT小鼠脂肪细胞体积的增加，但在ERα缺失的小鼠中并不减少，这与促红细胞生成素刺激的脂肪质量的减少无关。与WT对照组相比，EPO治疗还显著改善了雌性ERα−/−小鼠和雌性ERα脂肪KO的葡萄糖和胰岛素耐受性。促红细胞生成素的代谢活性增加与白色脂肪细胞的褐化有关，表现为白色脂肪相关基因的减少和棕色脂肪特异性解偶联蛋白1(UCP1)的诱导。这项研究明确了雌激素信号在修饰EPO调节葡萄糖代谢中的作用，以及不同性别的EPO对脂肪质量调节的作用。促红细胞生成素和雌激素之间的相互作用与雌性小鼠的代谢平衡和体重调节有关。在高脂饮食中，促红细胞生成素调节雄性小鼠的脂肪质量，但不调节雌性小鼠的脂肪质量。女性雌激素受体α缺失可恢复促红细胞生成素脂肪质量调节。雌激素受体α缺失增加了促红细胞生成素对糖耐量的调节。促红细胞生成素减少白色脂肪相关基因和增加解偶联蛋白1。促红细胞生成素和雌激素的相互作用与代谢稳态有关。
Erythropoietin (EPO), the cytokine required for erythropoiesis, contributes to metabolic regulation of fat mass and glycemic control. EPO treatment in mice on high-fat diets (HFD) improved glucose tolerance and decreased body weight gain via reduced fat mass in males and ovariectomized females. The decreased fat accumulation with EPO treatment during HFD in ovariectomized females was abrogated with estradiol supplementation, providing evidence for estrogen-related gender-specific EPO action in metabolic regulation. In this study, we examined the cross-talk between estrogen mediated through estrogen receptor α (ERα) and EPO for the regulation of glucose metabolism and fat mass accumulation. Wild-type (WT) mice and mouse models with ERα knockout (ERα−/−) and targeted deletion of ERα in adipose tissue (ERαadipoKO) were used to examine EPO treatment during high-fat diet feeding and after diet-induced obesity. ERα−/− mice on HFD exhibited increased fat mass and glucose intolerance. EPO treatment on HFD reduced fat accumulation in male WT and ERα−/− mice and female ERα−/− mice but not female WT mice. EPO reduced HFD increase in adipocyte size in WT mice but not in mice with deletion of ERα independent of EPO-stimulated reduction in fat mass. EPO treatment also improved glucose and insulin tolerance significantly greater in female ERα−/− mice and female ERαadipoKO compared with WT controls. Increased metabolic activity by EPO was associated with browning of white adipocytes as shown by reductions in white fat-associated genes and induction of brown fat-specific uncoupling protein 1 (UCP1). This study clearly identified the role of estrogen signaling in modifying EPO regulation of glucose metabolism and the sex-differential EPO effect on fat mass regulation. Cross-talk between EPO and estrogen was implicated for metabolic homeostasis and regulation of body mass in female mice. Erythropoietin regulates fat mass in male but not female mice on high-fat diets. Female estrogen receptor alpha deletion restores erythropoietin fat mass regulation. Estrogen receptor alpha deletion increases erythropoietin regulation of glucose tolerance. Erythropoietin reduced white fat-associated genes and increased uncoupling protein 1. Erythropoietin and estrogen cross-talk is implicated for metabolic homeostasis.